**10.1 miRNA regulation of T cells**

As a critical role of miRNA post transcriptional regulation in transformation within immune cells show that these tiny molecules can reduce the expression of various genes by 3 orders of magnitude during maturation [140]. Studies showed that different miRNAs are involved in the thymocytes development by Dicer or Drosha knockouts experiments. Obstruction in the process consequential drop of mature Tαβ and natural killer T (NKT) cells [141]. In animals' helminthic studies, absence or presence of miR 155, showed that it can effect TH 2 differentiation involving apoptotic processes [131]. miRNA machinery knockout experiments demonstrate that some of the miRNA are of absolute requirement for Thymic development and peripheral function of nTreg cells. However, dicer knockout of Fox P3 cells consequences to nTreg cells without oppressive role. Treg cells can also transform into T follicular helper cells that resulted in loss of immunomodulation and B cell activation in this scenario miR 155 is a regulator of nTreg cells. It should be remembered that miR 155 is expressed in all adaptive immune cells [142]. The expression and formation of active miR 181a is found to be tightly regulated intrathymic T cell development. The activities modulates the T cell antigen receptor (TCR) retort the down regulation through phosphatases which plays pivotal role in reducing TCR cell signaling. Thus the activities of miR 181a acts to modulates of TCR sensitivity towards T cell development in the lymphoid organ [131]. Blockage with antagomir (oligonucleotide) to miR 126 reduces the differentiation of TH 2 which are linked to helminthic pathogenesis during innate immune system activation. During this impasse, TH 17 cells regulate another miR 326 within their reach by up regulation [143]. These cells are differentiated and regulated by cytokine IL 23 [144]. It is shown that miR 17 polarizes then TH 2 cells, required in type 2 immune response to helminthes infection [141]. Mature TH cells are further influenced by miR 182 in response to IL 2 cytokine synthesis. This regulation is

post transcriptionally controlled with transcriptional factor Foxo 1 [145]. The ILC 2 bundle of cells are differentiated by GATA 3 factor, as discussed above. This transcriptional factor induces TH 2 differentiation and produces larger quantities of IL 4, IL-5, and IL-10 *in vivo* and IL 13 [31, 141]. It is documented that miR 126 regulation effects TH 2 polarization. In mice, an activator of transcription is targeted through POU 2F3. Furthermore, PU-1 significantly inhibits specific binding GATA 3 factor. Another molecule of interest is miR 126 where *in vivo* studies proved that it reduces TH 2 cells to specifically allergy promoting dust mite antigens [146]. miRNA machinery knockout experiments demonstrate that some of the miRNA are of absolute requirement for thymic development and peripheral function of nTreg cells. However, dicer knockout of Fox P3 cells consequence to nTreg cells but without oppressive role. Treg cells can also transform into T follicular helper cells that resulted in loss of immunomodulation and B cell activation in this scenario miR 155 is a regulator of nTreg cells. The suppressive part of miRNAs by the Treg cells can act on two points; (i) Treg regulating themselves, (ii) modified response of target cells on Treg cells [147].

### **10.2 miRNA regulation of B cells**

Like T cell lineage, B cells also are tangled up with various miRNA classes that regulate their differentiation and development within the bone marrow. The miR 181 overexpression in hematopoietic bone marrow increase in the fraction of B cell subtypes. Similarly miR 150 effect the B cell development at pro- and pre-B cell transformation due the apoptosis. Knockdown miR 155 mice reveals skewed CD 4 T cell polarization in the TH 2 subset [141]. B cell studies show that two miRNA, miR 155-5p and miR 155-3p, are expressed solely in these cells [148]. These miRNAs are positioned in Integration Cluster gene (BIC) area that positively prompt to various stimuli within the immune system [149]. Germline studies on miR-155 showed that its deletion induces reduction of B cell germinal centers [131, 150]. In mice, upregulation of miR 34a in the progenitor cells are acknowledged. Constitutively miR 34a expressed in B cell studies conclude that it block differentiation of pro-B to its next stage of pro-B cell and to mature B cell. The disparity occurs through Foxp 1 [148, 150]. Number of expression profile studies show that dysregulation is found for miR 182, miR 96, miR 183, miR 31 and miR 155 that effects B- and T-cells. Recent finding on miR 150, miR 127 and miR 379 also showed that there upregulation effects splenic maturation processes. The miR 150 levels are predominantly present in both B-cells and T-cells not on to their progenitors. On the other hand, miR 15 activities that it correlates to autoantibody production [150]. Another regulator The miR 17, encode several miRNAs from same transcript, also show that it negatively influences on pro- and pre-B transition through a blockage of BIM accumulation [131, 150]. Another protein, BMI 1—a ring finger structure, also promotes differentiation of TH 2 in a mouse model that in return stabilizes GATA 3 protein for transcription by protecting it from ubiquitination [141].

### **10.3 miRNA regulation of cell cycle**

Numerous citations show that cell cycle of T cells are directly regulated by miRNAs profile. The regulation is associated cell cycle check points through Cyclin T1 levels in Mϕ. It is documented that miR 182, as shown above, functions on expression of generalized transcriptional regulator, FoxO 1. This control regulates CD 4 T cell expansion with Cdk inhibitor, p27Kip1. Negative feedback on FoxO 1 is accomplish by miR 182. These signals activate IL 2. This induction results in TH 1, TH 2, TH 17 and naïve CD 4 cells expansion. Studies *in vitro* and *in vivo* showed that in a feedback loop, down regulation of miR 182 results in stoppage of spreading

**175**

*Goat Immunity to Helminthes*

*DOI: http://dx.doi.org/10.5772/intechopen.91189*

**10.4 Helminth vaccines in focus**

(i) attenuated and (ii) hidden antigen [159].

**10.5 Attenuated vaccines**

**10.6 Hidden antigens vaccines**

is one of the hallmark of helminthes infection [141, 151].

out of CD 4 cells [127, 141]. The nearly all vertebrates, immune system evolved itself to a finely fine-tune, an extraordinarily flexible apparatus within the host defense [125]. Besides direct role of various miRNAs, indirect regulation is also well in place in immune system. This is seen for miR 19a, miR 19b in the miR 17 cluster. These two sequence encode deubiquitylation enzyme, CYC D, which blocks NF-κB activities. Its expression results in Cyclin and other growth factors. In a recent documentation that there is a universal reduction of CD 4 T cells which

Global data on parasitic helminthes speaks loudly of the livestock diseases that affect many area of the world, including Europe. Their infections are related to huge economic losses in loss of fertility, production and body weight [152]. Cumulative responsible statistics show that more than 55% of livestock suffer from these infections outcome. It causes diseases in Europe and cause highly significant losses in productivity and welfare in animals and then in humans and welfare problems globally. Yearly estimates show that in liver fluke (*Fasciola hepatica*) infections up to US \$3 billion per annum are lost [153]. Conservative estimates in the United Kingdom show that gastrointestinal (GI) helminthic infections to sheep industry shares losses of more than £84 million per annum [154]. These infections are traditionally controlled by administration of various anthelmintic drugs [155]. Naïve practice resulted in development of resistance to these medicines. Recent documentations for sheep farming, particularly in New Zealand, Australia and Brazil, showed that Multi Drug resistance (MDR) is much elaborative phenomenon worldwide and have upward trend [156]. Development of these vaccines started some 50 years ago. Most helminth component formulating and their administration showed that they effectively interrupt the dynamic morphological and antigenic changes during parasites life cycle of the worms and can be used as controlling tool [157]. Many helminthes share much sophisticated evasive immune mechanism that is discussed already in detail. This quality of worms make them very hard for scientists to move forward to develop efficient vaccine candidates [158]. Many efforts to develop anthelminthic vaccines in livestock started many years back with limited success [159]. As discussed in detail above, elusive behavior of worms does not provide adequate long-lasting protection at all stages of helminthic maturation [160]. Vaccines provide manifold benefits on improving animal health, welfare and control of animal infection. The use of vaccine also addresses resistance to acaricides, antibiotics and anthelminthic medicinal solutions [158]. At present, there tend to be two strategies to effectively develop vaccine;

These vaccines are developed and used after irradiating L3 larval stage that prevents development of mature adult worms. This protection could reach up to 98% *in vitro* with two experimental doses. Attenuated larval *Dictyocaulus filaria* (sheep lungworm) name "DIFIL" for *Dictyocaulus filaria* larva is effectively used in India

Helminthic recombinant integral membrane proteins, part of worm gut, that whenever used provoke high degree of immune recognition and type 1 and type 2

since 1981 [160]. A similar approaches are used to develop other vaccines.

### *Goat Immunity to Helminthes DOI: http://dx.doi.org/10.5772/intechopen.91189*

*Goats (Capra) - From Ancient to Modern*

target cells on Treg cells [147].

**10.2 miRNA regulation of B cells**

**10.3 miRNA regulation of cell cycle**

post transcriptionally controlled with transcriptional factor Foxo 1 [145]. The ILC 2 bundle of cells are differentiated by GATA 3 factor, as discussed above. This transcriptional factor induces TH 2 differentiation and produces larger quantities of IL 4, IL-5, and IL-10 *in vivo* and IL 13 [31, 141]. It is documented that miR 126 regulation effects TH 2 polarization. In mice, an activator of transcription is targeted through POU 2F3. Furthermore, PU-1 significantly inhibits specific binding GATA 3 factor. Another molecule of interest is miR 126 where *in vivo* studies proved that it reduces TH 2 cells to specifically allergy promoting dust mite antigens [146]. miRNA machinery knockout experiments demonstrate that some of the miRNA are of absolute requirement for thymic development and peripheral function of nTreg cells. However, dicer knockout of Fox P3 cells consequence to nTreg cells but without oppressive role. Treg cells can also transform into T follicular helper cells that resulted in loss of immunomodulation and B cell activation in this scenario miR 155 is a regulator of nTreg cells. The suppressive part of miRNAs by the Treg cells can act on two points; (i) Treg regulating themselves, (ii) modified response of

Like T cell lineage, B cells also are tangled up with various miRNA classes that regulate their differentiation and development within the bone marrow. The miR 181 overexpression in hematopoietic bone marrow increase in the fraction of B cell subtypes. Similarly miR 150 effect the B cell development at pro- and pre-B cell transformation due the apoptosis. Knockdown miR 155 mice reveals skewed CD 4 T cell polarization in the TH 2 subset [141]. B cell studies show that two miRNA, miR 155-5p and miR 155-3p, are expressed solely in these cells [148]. These miRNAs are positioned in Integration Cluster gene (BIC) area that positively prompt to various stimuli within the immune system [149]. Germline studies on miR-155 showed that its deletion induces reduction of B cell germinal centers [131, 150]. In mice, upregulation of miR 34a in the progenitor cells are acknowledged. Constitutively miR 34a expressed in B cell studies conclude that it block differentiation of pro-B to its next stage of pro-B cell and to mature B cell. The disparity occurs through Foxp 1 [148, 150]. Number of expression profile studies show that dysregulation is found for miR 182, miR 96, miR 183, miR 31 and miR 155 that effects B- and T-cells. Recent finding on miR 150, miR 127 and miR 379 also showed that there upregulation effects splenic maturation processes. The miR 150 levels are predominantly present in both B-cells and T-cells not on to their progenitors. On the other hand, miR 15 activities that it correlates to autoantibody production [150]. Another regulator The miR 17, encode several miRNAs from same transcript, also show that it negatively influences on pro- and pre-B transition through a blockage of BIM accumulation [131, 150]. Another protein, BMI 1—a ring finger structure, also promotes differentiation of TH 2 in a mouse model that in return stabilizes GATA 3 protein for transcription by protecting it from ubiquitination [141].

Numerous citations show that cell cycle of T cells are directly regulated by miRNAs profile. The regulation is associated cell cycle check points through Cyclin T1 levels in Mϕ. It is documented that miR 182, as shown above, functions on expression of generalized transcriptional regulator, FoxO 1. This control regulates CD 4 T cell expansion with Cdk inhibitor, p27Kip1. Negative feedback on FoxO 1 is accomplish by miR 182. These signals activate IL 2. This induction results in TH 1, TH 2, TH 17 and naïve CD 4 cells expansion. Studies *in vitro* and *in vivo* showed that in a feedback loop, down regulation of miR 182 results in stoppage of spreading

**174**

out of CD 4 cells [127, 141]. The nearly all vertebrates, immune system evolved itself to a finely fine-tune, an extraordinarily flexible apparatus within the host defense [125]. Besides direct role of various miRNAs, indirect regulation is also well in place in immune system. This is seen for miR 19a, miR 19b in the miR 17 cluster. These two sequence encode deubiquitylation enzyme, CYC D, which blocks NF-κB activities. Its expression results in Cyclin and other growth factors. In a recent documentation that there is a universal reduction of CD 4 T cells which is one of the hallmark of helminthes infection [141, 151].
